Medical sequencing is a new approach to discovery of the genetic causes of complex disorders. Medical sequencing refers to the brute-force sequencing of the genome or transcriptome of individuals affected by a disease or with a trait of interest. Dissection of the cause of common, complex traits is anticipated to have an immense impact on the biotechnology, pharmaceutical, diagnostics, healthcare and agricultural biotech industries. In particular, it is anticipated to result in the identification of novel diagnostic tests, novel targets for drug development, and novel strategies for breeding improved crops and livestock animals. Medical sequencing has been made possible by the development of transformational, next generation DNA sequencing instruments, developed by 454 Life Sciences/Roche Diagnostics, Applied Biosystems/Agencourt, Illumina/Solexa and Helicos, these instruments are anticipated to increase the speed and throughput of DNA sequencing by 3000-fold (to 2 billion base pairs of DNA sequence per instrument per experiment).
Common, conventional approaches to the discovery of the genetic basis of complex disorders include the use of linkage disequilibrium to identify quantitative trait loci in studies of multiple sets of affected pedigrees, candidate gene-based association studies in cohorts of affected and unaffected individuals that have been matched for confounding factors such as ethnicity, and whole genome genotyping studies in which associations are sought between linkage disequilibrium segments (based upon tagging SNP genotypes or haplotypes), and diagnosis in cohorts of affected and unaffected individuals that have been matched for confounding factors.
These methods are based on the assumption that complex disorders share underlying genetic components (i.e. are largely genetically homogeneous). In other words, while complex diseases result from the cumulative impact of many genetic factors, those factors are largely the same in individuals. While this assumption has met with some success, there are numerous cases where this commonality has failed. Progress in dissecting the genetics of complex disorders using these approaches has been slow and limited. Software systems for DNA sequence variant discovery operating under this assumption are inadequate for next-generation DNA sequencing technologies that feature short read lengths, novel base calling and quality score determination methods, and relatively high error rates.